Adipocyte-specific Expression of Murine Resistin Is Mediated by Synergism between Peroxisome Proliferator-activated Receptor γ and CCAAT/Enhancer-binding Proteins

Tomaru, Takuya; Steger, David J.; Lefterova, Martina I.; Schupp, Michael; Lazar, Mitchell A.

doi:10.1074/jbc.m808407200

Cited by 74 publications

(50 citation statements)

References 73 publications

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“…1a). Similar results were obtained from our analyses of the other adipose genes aP2, Resistin, Catalase and PEPCK [19][20][21][22][23][24] . We observed region-specific demethylation adjacent to the PPREs in these genes similar to that found in Plin1 ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 77%

PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

et al. 2013

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Recent studies have shown that DNA demethylation goes through the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by Tet proteins. However, it is still unclear how the target regions for demethylation are distinguished within their genomic context. Here we show that the nuclear receptor peroxisome proliferator-activated receptor-g (PPARg) has the ability to direct local demethylation around its binding sites, the PPAR response elements (PPREs), during adipocyte differentiation. PPARg is a key regulator of the differentiation process that forms a PPARg co-activator complex on PPREs and activates the expression of adipocyte-specific genes. The complex is poly(ADP-ribosyl)ated (PARylated) on PPREs, and Tet proteins catalyse the conversion of 5mC to 5hmC locally by their ability to bind to the PAR polymer, thereby inducing region-specific demethylation. Our study demonstrates that a sequence-dependent transcription factor complex can, through its posttranslational modification, serve for Tet proteins as a landmark to identify sites of DNA demethylation.

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Section: Resultssupporting

confidence: 77%

PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

et al. 2013

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“…Indeed, our previous studies mapping histone modifications in 3T3-L1-differentiated adipocytes identified intergenic regions enriched for histone marks that colocalize with PPARg and CEBPa and confer enhancer activity Tomaru et al 2009). Therefore, to identify potential cis-acting sequences controlling adipoctye differentiation, we combined chromatin immunoprecipitation with microarray analysis (ChIP-chip) to map histone modifications at high resolution during different stages of adipogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…Each has increased acetylation at day 1 relative to day 0, and all but the region upstream of Pparg1 have more acetylation at day 1 compared with day 10. Acetylation remains high on day 10 upstream of Pparg1, with a level similar to the Retn enhancer (Tomaru et al 2009), possibly because PPARg and CEBPa occupy both regions in adipocytes. CEBPb drives 3T3-L1 differentiation before CEBPa, and CEBPb ChIP revealed variable levels of occupancy for each region at day 0 that increase at day 1 for all and decrease by day 10 for most ( Fig.…”

Section: Identification Of Gr and Cebpb At A Subset Of Genomic Regionmentioning

confidence: 99%

Propagation of adipogenic signals through an epigenomic transition state

Steger¹,

Grant²,

Schupp³

et al. 2010

Genes Dev.

Self Cite

222

221

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The transcriptional mechanisms by which temporary exposure to developmental signals instigates adipocyte differentiation are unknown. During early adipogenesis, we find transient enrichment of the glucocorticoid receptor (GR), CCAAT/enhancer-binding protein b (CEBPb), p300, mediator subunit 1, and histone H3 acetylation near genes involved in cell proliferation, development, and differentiation, including the gene encoding the master regulator of adipocyte differentiation, peroxisome proliferator-activated receptor g2 (PPARg2). Occupancy and enhancer function are triggered by adipogenic signals, and diminish upon their removal. GR, which is important for adipogenesis but need not be active in the mature adipocyte, functions transiently with other enhancer proteins to propagate a new program of gene expression that includes induction of PPARg2, thereby providing a memory of the earlier adipogenic signal. Thus, the conversion of preadipocyte to adipocyte involves the formation of an epigenomic transition state that is not observed in cells at the beginning or end of the differentiation process. Transcription factors control cell fate decisions by programming the expression of large gene sets, often through mechanisms impacting the post-translational modification of histone proteins in chromatin (Allis et al. 2007). Genome-wide changes to histone modification patterns occur as cells differentiate, such that distinct epigenomes are present in different cell types (Bernstein et al. 2007). A cell's epigenome is thought to be involved in establishing its identity, yet whether histone modifications transmit the memory of a given cell state or implement the memory once it is transmitted by a distinct mechanism is currently unclear.The epigenomic factors controlling adipocyte cell differentiation are not known. Adipocytes, the major fatcontaining component of adipose tissue, are terminally differentiated cells derived from mesenchymal precursors (Ailhaud et al. 1992). Study of adipocyte precursors in vivo is difficult because adipose tissue in rodents is undetectable macroscopically until shortly before birth.Thus, most of what is known about the molecular basis of adipocyte differentiation derives from tissue culture models, one of the best characterized being the mouse 3T3-L1 model Kehinde 1975, 1976). Temporary exposure to a mix of insulin, glucocorticoid, and an inducer of cAMP signaling triggers adipogenesis, changing the expression of hundreds of genes, including a variety of transcription factors that regulate one another as well as structural genes (Farmer 2006). One of these encodes peroxisome proliferator-activated receptor g (PPARg), a sequence-specific transcription factor that is necessary (Barak et al. 1999;Kubota et al. 1999;Rosen et al. 1999) and sufficient (Tontonoz et al. 1994;Hu et al. 1995;Shao and Lazar 1997) for adipogenesis, and is hence termed the master regulator (Rosen et al. 2002). CCAAT/ enhancer-binding protein (CEBP) transcriptional regulators also play a major role, and each can induce adip...

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“…In addition, at least some target genes have been shown to be activated by both transcription factors (19)(20)(21)(22)(23)(24)(25). More recent genome-wide profiling of C/EBP␣ and PPAR␥ binding sites using chromatin immunoprecipitation (ChIP) combined with microarray analysis (ChIP-chip) or deep sequencing (ChIPseq) have shown that most adipocyte genes in murine adipocytes are associated with binding of both factors (26)(27)(28), indicating that a hitherto unrecognized high number of genes are regulated by both PPAR␥ and C/EBP␣.…”

mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

Madsen

Siersbæk

Boergesen

et al. 2014

Molecular and Cellular Biology

215

160

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) and CCAAT/enhancer binding protein ␣ (C/EBP␣) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPAR␥ and C/EBP␣ binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between PPAR␥ and C/EBP␣ at shared binding sites, we established a fibroblastic model system in which PPAR␥ and C/EBP␣ can be independently expressed. Using RNA sequencing, we demonstrate that coexpression of PPAR␥ and C/EBP␣ leads to synergistic activation of many key metabolic adipocyte genes. This is associated with extensive C/EBP␣-mediated reprogramming of PPAR␥ binding and vice versa in the vicinity of these genes, as determined by chromatin immunoprecipitation combined with deep sequencing. Our results indicate that this is at least partly mediated by assisted loading involving chromatin remodeling directed by the leading factor. In conclusion, we report a novel mechanism by which the key adipogenic transcription factors, PPAR␥ and C/EBP␣, cooperate in activation of the adipocyte gene program. The conversion of preadipocytes to mature fat-laden adipocytes involves a complex network of transcription factors that have been shown to act in two waves (1-4). The adipogenic cocktail used to stimulate in vitro differentiation of preadipocytes induces the first wave of factors that then subsequently induce the second wave of adipogenic transcription factors. Key components of this second wave are peroxisome proliferator-activated receptor ␥ (PPAR␥) and CCAAT/enhancer binding protein ␣ (C/EBP␣), each of which has been shown to directly promote expression of the adipocyte gene program. In particular, several ex vivo and in vivo studies have demonstrated that PPAR␥ is obligate for adipogenesis (5-7) as well as maintenance of the adipocyte phenotype (8). Similarly, several in vivo models have demonstrated the importance of C/EBP␣ for differentiation and maintenance of white adipose tissue (9-11). C/EBP␣ is also important for ex vivo differentiation of adipocytes, although it is not strictly required for adipocyte differentiation in the presence of ectopic PPAR␥ expression (12). Furthermore, C/EBP␣ has been reported to be specifically involved in activating the gene program driving insulinstimulated glucose uptake (13,14).It is well established that PPAR␥ and C/EBP␣ cooperate to accelerate adipogenesis (12, 15) through their mutual induction of each other (14,(16)(17)(18). In addition, at least some target genes have been shown to be activated by both transcription factors (19-25). More recent genome-wide profiling of C/EBP␣ and PPAR␥ binding sites using chromatin immunoprecipitation (ChIP) combined with microarray analysis (ChIP-chip) or deep sequencing (ChIPseq) have shown that most adipocyte genes in murine adipocytes are associate...

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Adipocyte-specific Expression of Murine Resistin Is Mediated by Synergism between Peroxisome Proliferator-activated Receptor γ and CCAAT/Enhancer-binding Proteins

Cited by 74 publications

References 73 publications

PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

Propagation of adipogenic signals through an epigenomic transition state

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

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